1. Medicines for the Treatment of Obesity “But Doc, isn’t there a pill I can take?” Joanna Ruchala, MD

2. Outline Case Presentation Case Presentation Definition, Prevalence, & Comorbidities of Obesity Definition, Prevalence, & Comorbidities of Obesity Indications for Drug Therapy Indications for Drug Therapy FDA Approved Medicines for Obesity Treatment FDA Approved Medicines for Obesity Treatment sibutramine, phentermine, orlistat sibutramine, phentermine, orlistat Other Medicines that Promote Weight Loss Other Medicines that Promote Weight Loss DM medicines, antidepressants (SSRIs), anti-epileptics DM medicines, antidepressants (SSRIs), anti-epileptics Investigational Medicines: Rimonabant Investigational Medicines: Rimonabant Summary and Case discussion Summary and Case discussion

3. Case: DB 49 y/o obese woman with the following concerns: Chronic bilateral knee pain not responding to anti-inflammatory medications Chronic bilateral knee pain not responding to anti-inflammatory medications Inability to exercise due to pain Inability to exercise due to pain Inability to loose weight despite food restriction Inability to loose weight despite food restriction

4. DB PMH Morbid obesity Morbid obesity HTN HTN Hyperlipidemia Hyperlipidemia  TG,  HDL  TG,  HDL OSA (Can’t use CPAP) OSA (Can’t use CPAP) OA OA Depression Depression Insulin resistance Insulin resistance Hypothyroidism Hypothyroidism GERD GERD s/p cholecystectomy s/p cholecystectomy DB Medications Diclofenac Lasix Prevacid Levothyroxine Sertraline Benazepril DB Social History Disabled/ MA +tobacco, no alcohol

5. DB Exam Morbidly obese Morbidly obese 285 lb, 5’2”, BMI 52 285 lb, 5’2”, BMI 52 Knee exam difficult due to body habitus Knee exam difficult due to body habitus Diffuse tenderness Diffuse tenderness  ROM (0-100°)  ROM (0-100°) No ligamentous laxity No ligamentous laxity +Retropatellar crepitus +Retropatellar crepitus DB Imaging Data Standing Plain Films: Severe OA knees bilaterally Lateral compartment on R Medial compartment on L

6. DB Assessment & Plan Morbid obesity and severe bilateral OA of knees Morbid obesity and severe bilateral OA of knees Referred to Orthopedics Referred to Orthopedics TKA is indicated, IF she can reduce weight below 180 lbs. TKA is indicated, IF she can reduce weight below 180 lbs. Referred to Health ED for dietary counseling Referred to Health ED for dietary counseling Last seen in September, several “no shows.” Last seen in September, several “no shows.” Referred for possible Bariatric surgery Referred for possible Bariatric surgery WI Medicaid coverage as of 2/05 WI Medicaid coverage as of 2/05 Yes: Gastric bypass for qualified, low risk patients Yes: Gastric bypass for qualified, low risk patients No: Gastric banding No: Gastric banding DB asks whether there are any medications she could take to help her lose weight DB asks whether there are any medications she could take to help her lose weight

7. When diet and exercise are not effective, or adequate exercise is not possible, are there medications to treat obesity that are safe and effective? When diet and exercise are not effective, or adequate exercise is not possible, are there medications to treat obesity that are safe and effective? How do I determine which medications are right for which patients? How do I determine which medications are right for which patients? What about cost/ coverage by local insurance? What about cost/ coverage by local insurance? Questions

8. Definition of Obesity BMI 25-29.9 (Grade 1, overweight) BMI 25-29.9 (Grade 1, overweight) BMI 30-39.9 (Grade 2, obese) BMI 30-39.9 (Grade 2, obese) BMI > 40 (Grade 3, Morbidly obese) BMI > 40 (Grade 3, Morbidly obese) Increased visceral fat Increased visceral fat Waist > 94 cm in men (waist-to-hip > 0.95) Waist > 94 cm in men (waist-to-hip > 0.95) Waist > 80 cm in women (waist-to-hip >0.8) Waist > 80 cm in women (waist-to-hip >0.8)

9. Prevalence of Obesity More than 30% of adults in the US are overweight or obese, and this percentage is rising. Percentage of people with BMI ≥ 30 in the US in 2005 CDC’s Behavioral Risk Factor Surveillance System.

10. Obesity Related Comorbidities HTN/ hyperlipidemia CAD/CVA DM II Cancer (Breast, Colon, Prostate) Meralgia paresthetica Gallbladder disease NASH/ NAFLD GERD Varicose veins Endometrial Ca PCOS/ infertility Surgical Risk/ post-op complications LE edema/ cellulitis DepressionOA Pulmonary HTN/ OSA

11. Indications for Drug Therapy in Obesity Failure of diet and exercise alone Failure of diet and exercise alone Significant obesity related comorbidities even if BMI < 30 (ie 25-30). Significant obesity related comorbidities even if BMI < 30 (ie 25-30). No contraindications to drug therapy No contraindications to drug therapy Medication interactions Medication interactions Medical conditions that may be adversely affected by the obesity drug Medical conditions that may be adversely affected by the obesity drug Snow, et al, Ann Intern Med, 2005.

12. Sibutramine Mechanism of action: Mechanism of action: Inhibits norepinephrine and serotonin reuptake Inhibits norepinephrine and serotonin reuptake Decreases food intake; ?Thermogenic effect? Decreases food intake; ?Thermogenic effect? Dosing: 5 -15 mg po daily Dosing: 5 -15 mg po daily Schedule IV, but approved for long-term use Schedule IV, but approved for long-term use Cost: about $105 for a 30 day supply of 10 mg tablets Cost: about $105 for a 30 day supply of 10 mg tablets Insurance coverage: NC by Unity, PPlus, or Medicaid Insurance coverage: NC by Unity, PPlus, or Medicaid

13. Sibutramine: Efficacy Meta-analysis of healthy obese adults Meta-analysis of healthy obese adults Exclusion: patients with CAD Exclusion: patients with CAD Concomitant lifestyle, dietary, and behavioral modification Concomitant lifestyle, dietary, and behavioral modification Primary outcome: weight loss Primary outcome: weight loss Secondary outcomes: cardiovascular, metabolic Secondary outcomes: cardiovascular, metabolic Artburn, et al, Arch Intern Med, 2004. Dose # trials DurationPatients 10-15 mg 7 8-12 wks 546 12 (4-5-3) 16-24 wks 1079 5 44-54 wks 2188

14. Results: Mean Difference in Weight Loss Subgroup A used late-observation-carried-forward analysis and had >70% follow up Subgroup B analyzed only participants who completed the trial Subgroup C had follow up rates less than 70% ABC Artburn, et al, Arch Intern Med, 2004. 2.78 3.43 4.45

15. Secondary Outcomes Modest increase in BP and HR Modest increase in BP and HR Small improvements in TG, HDL, & glycemic control Small improvements in TG, HDL, & glycemic control No evidence of improvement of morbidity & mortality No evidence of improvement of morbidity & mortality No dose effect for weight loss. No dose effect for weight loss. 1 trial showed weight loss maintained at 2 yrs 1 trial showed weight loss maintained at 2 yrs 2 trials showed regain of 50% of weight at 6-12 months after stopping medicine. 2 trials showed regain of 50% of weight at 6-12 months after stopping medicine. Artburn, et al, Arch Intern Med, 2004.

16. Cochrane Review: Sibutramine Long-term Efficacy Meta-analysis of RCTs, Sibutramine vs. placebo Meta-analysis of RCTs, Sibutramine vs. placebo 3 trials -- weight loss at more than 1 year follow up 3 trials -- weight loss at more than 1 year follow up 2 trials -- weight maintenance at 2 years 2 trials -- weight maintenance at 2 years Inclusion: adults BMI>30 or BMI>27 + comorbidities Inclusion: adults BMI>30 or BMI>27 + comorbidities Exclusion: patients with DM or uncontrolled HTN Exclusion: patients with DM or uncontrolled HTN Results: 4.3 kg (3.6-4.9) more wt loss with sibutramine Results: 4.3 kg (3.6-4.9) more wt loss with sibutramine 27% more patients maintained 80% of original weight loss at 2 years with sibutramine 27% more patients maintained 80% of original weight loss at 2 years with sibutramine Adverse effects: Small increase in HR and BP Adverse effects: Small increase in HR and BP Padwal, et al. Cochrane Database of Systematic Reviews, 2003.

17. Sibutramine with & without Lifestyle Changes Wadden TA et al. NEJM, 2005. 224 obese adults randomized to the following for 1 year: 224 obese adults randomized to the following for 1 year: 15 mg sibutramine daily (PCP 8 visits, no counseling) 15 mg sibutramine daily (PCP 8 visits, no counseling) Lifestyle modification alone (30 group sessions, 90 minutes, psychologist) Lifestyle modification alone (30 group sessions, 90 minutes, psychologist) Sibutramine + lifestyle modification (30 group sessions) Sibutramine + lifestyle modification (30 group sessions) Sibutramine + brief lifestyle modification (PCP 8 visits, brief counseling) Sibutramine + brief lifestyle modification (PCP 8 visits, brief counseling) All prescribed diet 1200-1500 kcal per day and exercise regimen All prescribed diet 1200-1500 kcal per day and exercise regimen

18. Sibutramine Adverse Effects Contraindications Increase BP, HR History of CAD, CHF, CVA, glaucoma Palpitations, prolong QT Tachyarrhythmia (rare) History of arrhythmia Thrombocytopenia Predisposition to bleeding P450 metabolism Severe liver or renal disease Serotonin syndrome MAOIs, SSRIs HA, insomnia, Sz (rare) History of seizure GI disturbance

19. Phentermine and Diethylpropion Mechanism of action: Stimulate NE release and inhibit re-uptake Mechanism of action: Stimulate NE release and inhibit re-uptake Dosing (short-term use only -- < 12 weeks) Dosing (short-term use only -- < 12 weeks) 18.75 to 37.5 mg once daily or in divided doses 18.75 to 37.5 mg once daily or in divided doses Schedule IV Schedule IV Cost: about $34 for a month supply of 37.5 mg tablets Cost: about $34 for a month supply of 37.5 mg tablets Insurance coverage: NC by Unity, PPlus, or Medicaid Insurance coverage: NC by Unity, PPlus, or Medicaid

20. Phentermine: Efficacy and Safety Meta-analysis: Included 6 RCTs Meta-analysis: Included 6 RCTs Duration: 2-24 wks Duration: 2-24 wks Dose: 15-30 mg per day Dose: 15-30 mg per day Results: 3.6kg (0.6-6.0) more wt loss with phentermine Results: 3.6kg (0.6-6.0) more wt loss with phentermine No data on side effects or adverse events reported No data on side effects or adverse events reported Haddock et al, J Obes Relat Metabolic Disord, 2002.

21. Phentermine Adverse Effects HTN, tachyarrhythmia Heart valve disorder (rare) PPH (rare) GI disturbance Psychosis, agitation HA, insomnia, tremor, AMS, dizziness Decreased libido Affect insulin needs in DM Contraindications CAD, HTN, glaucoma Hyperthyroidism MAOI, SSRI History of drug/etoh abuse Psychiatric disease

22. Orlistat Mechanism of Action Mechanism of Action Inhibits pancreatic lipases preventing hydrolysis of ingested fat Inhibits pancreatic lipases preventing hydrolysis of ingested fat Less than 1% absorbed Less than 1% absorbed Dosing: 60 – 120 mg prior to each meal. Dosing: 60 – 120 mg prior to each meal. Lower dose OTC (My Alli) Lower dose OTC (My Alli) Cost: about $224 for a 1 month supply of 120 mg dose Cost: about $224 for a 1 month supply of 120 mg dose Insurance coverage: NC by Unity, PPlus, or Medicaid Insurance coverage: NC by Unity, PPlus, or Medicaid GI side effects: diarrhea, cramping, flatus, oily discharge, malabsorption of fat soluble vitamins. GI side effects: diarrhea, cramping, flatus, oily discharge, malabsorption of fat soluble vitamins. Only drug interaction: CSA Only drug interaction: CSA

23. Orlistat: Efficacy Meta-analysis, 29 RCTs included Meta-analysis, 29 RCTs included 12 trials with 6 months follow up 12 trials with 6 months follow up Mean of 2.59 kg (1.74-3.46) more wt loss with orlistat Mean of 2.59 kg (1.74-3.46) more wt loss with orlistat 22 trials with 12 months follow up 22 trials with 12 months follow up Mean of 2.89 kg (2.27-3.51) more wt loss with orlistat Mean of 2.89 kg (2.27-3.51) more wt loss with orlistat RR diarrhea 3.40, flatus 3.10, and dyspepsia 1.48 RR diarrhea 3.40, flatus 3.10, and dyspepsia 1.48 No difference between 6 and 12 months No difference between 6 and 12 months Cochrane review meta-analysis Cochrane review meta-analysis 11 trials with at least 12 months follow up 11 trials with at least 12 months follow up Mean of 2.7 kg (2.3-3.1) more wt loss with orlistat Mean of 2.7 kg (2.3-3.1) more wt loss with orlistat Li, et al. Ann Intern Med, 2005. Padwal, et al. Cochrane Database of Systematic Reviews, 2003.

24. Orlistat: Long-term Efficacy 4-year double blind placebo controlled RCT 4-year double blind placebo controlled RCT 3,305 patients, BMI>30 3,305 patients, BMI>30 Lifestyle changes + orlistat (120 mg) or placebo Lifestyle changes + orlistat (120 mg) or placebo Primary outcomes: wt loss, time to onset DM II Primary outcomes: wt loss, time to onset DM II Mean of 2.8 kg more wt loss with orlistat (P<0.001) Mean of 2.8 kg more wt loss with orlistat (P<0.001) Incidence of diabetes 6.2% vs 9% (P=0.0032) Incidence of diabetes 6.2% vs 9% (P=0.0032) Torgerson, et al. Diabetes Care, 2004.

25. Combination Therapy 3 small trials 3 small trials 34 women after 1 year on sibutramine with 11.6% mean wt loss randomized to S+O or S + placebo for 16 wks 34 women after 1 year on sibutramine with 11.6% mean wt loss randomized to S+O or S + placebo for 16 wks 89 women randomized to diet+O, diet+S, or diet+O+S for 6 months 89 women randomized to diet+O, diet+S, or diet+O+S for 6 months 86 pts randomized to S, O, S+O, or diet for 12 wks 86 pts randomized to S, O, S+O, or diet for 12 wks Sibutramine alone as good as Combination & better than Orlistat alone Sibutramine alone as good as Combination & better than Orlistat alone Wadden et al. Obes Res, 2000. Kaya et al. Biomed Phamacother, 2004. Sari et al. Endocrin Res, 2004.

26. Li, Z. et. al. Ann Intern Med 2005;142:532-546 Weight loss with bupropion & fluoxetine vs. placebo at 6 - 12 months Antidepressants: Efficacy Note: High doses used Fluoxetine 60 mg daily Bupropion 400 mg/day

27. Weight loss with topiramate versus placebo at 6 months Li, Z. et. al. Ann Intern Med 2005;142:532-546 Antiepileptic: Efficacy Note: High dose, 192 mg/day

28. Metformin 3234 nondiabetic adults with impaired glucose tolerance 3234 nondiabetic adults with impaired glucose tolerance Mean BMI 34, mean age 51, 68% women Mean BMI 34, mean age 51, 68% women Randomized to placebo, metformin 850 mg po BID or lifestyle changes for 2.8 years Randomized to placebo, metformin 850 mg po BID or lifestyle changes for 2.8 years Knowler et al. NEJM 2002.

29. Metformin Compared to Others 150 women with BMI >30 randomized to the following 150 women with BMI >30 randomized to the following Sibutramine 10 mg po BID (Higher than normal dose) Sibutramine 10 mg po BID (Higher than normal dose) Orlistat 120 mg po TID Orlistat 120 mg po TID Metformin 850 mg po BID Metformin 850 mg po BID All groups also with lifestyle interventions/ nutrition counseling All groups also with lifestyle interventions/ nutrition counseling No placebo group No placebo group 6 months follow up 6 months follow up % decrease BMI % decrease waist circumference Sibutramine13.5710.43 Orlistat9.096.64 Metformin9.908.10 Gokcel A, et al. Diab Obes Metab 2002.

30. Exenatide 336 pts, BMI 34.2+/-5.9 336 pts, BMI 34.2+/-5.9 DM II, mean A1c 8.2+/- 1.1 DM II, mean A1c 8.2+/- 1.1 4 wks placebo 4 wks placebo 4 wks 5  g exenatide BID or placebo 4 wks 5  g exenatide BID or placebo 26 wks 5 or 10  g exenatide BID or placebo 26 wks 5 or 10  g exenatide BID or placebo All on metformin All on metformin End of study mean A1c 7.4% End of study mean A1c 7.4% 50% reached goal of < 7% on 10  g dose 50% reached goal of < 7% on 10  g dose DeFronzo RA, et al. Diab Care, 2005.

31. Pi-Sunyer, F. X. et al. JAMA 2006. Rimonabant Cannabinoid-1 receptor blocker Cannabinoid-1 receptor blocker Reduces overactivation of the central & peripheral endocannabinoid system Reduces overactivation of the central & peripheral endocannabinoid system 3045 pts with BMI>27 and HTN or dyslipidemia 3045 pts with BMI>27 and HTN or dyslipidemia 4-wk single blind placebo + diet run-in 4-wk single blind placebo + diet run-in Randomized to 5 mg daily, 20 mg daily, or placebo for 1 year Randomized to 5 mg daily, 20 mg daily, or placebo for 1 year Treated pts re-randomized to placebo or continued rimonibant for 2nd year Treated pts re-randomized to placebo or continued rimonibant for 2nd year High drop out rate~ 50% in all groups High drop out rate~ 50% in all groups Most common side effect was nausea (11.2% vs 5.8%) Most common side effect was nausea (11.2% vs 5.8%)

32. Surgery vs. Pharmacotherapy RCT, 80 adults BMI 30-35 RCT, 80 adults BMI 30-35 Laparoscopic adjustable gastric banding Laparoscopic adjustable gastric banding Intensive non-surgical program Intensive non-surgical program Very low calorie diet (500-550 kcal/day) X 12 wks Very low calorie diet (500-550 kcal/day) X 12 wks Orlistat 120 mg added before some meals X 4 wks Orlistat 120 mg added before some meals X 4 wks Orlistat before all meals X 8 wks for total of 6 mo Orlistat before all meals X 8 wks for total of 6 mo Continued low calorie diet or orlistat + behavioral therapy for long-term maintenance Continued low calorie diet or orlistat + behavioral therapy for long-term maintenance Primary endpoint: Change in weight Primary endpoint: Change in weight O'Brien, P. E. et. al. Ann Intern Med 2006;144:625-633

33. Mean % of initial weight lost (initial data carried forward for missing values) Statistically significant improvement in metabolic syndrome in surgical group: 35% of pts in both groups initially, 24% of pts in non-surgical group and 3% of pts in surgical group at 2 yrs Statistically significant improvement in metabolic syndrome in surgical group: 35% of pts in both groups initially, 24% of pts in non-surgical group and 3% of pts in surgical group at 2 yrs Surgical group adverse events: 1 port site infection, 4 prolapse of posterior gastric wall, 1 cholecystitis Surgical group adverse events: 1 port site infection, 4 prolapse of posterior gastric wall, 1 cholecystitis Non-surgical group adverse events: 1 diet intolerance, 8 orlistat intolerance, 4 cholecystitis Non-surgical group adverse events: 1 diet intolerance, 8 orlistat intolerance, 4 cholecystitis

34. Summary Weight loss with obesity medicines is modest Weight loss with obesity medicines is modest Obesity medicines are not a substitute for diet and exercise Obesity medicines are not a substitute for diet and exercise Weight loss is often not maintained after drug is discontinued Weight loss is often not maintained after drug is discontinued Most obesity medicines are not covered by insurance Most obesity medicines are not covered by insurance Drug Wt loss Sibutramine 4-5 kg Phentermine 3-4 kg Orlistat 2-3 kg Metformin 2 kg Exenatide 2-3 kg Bupropion FluoxetineMixed Topamax 6-7 kg Rimonabant

35. Selecting a Medicine for Obesity Treatment Cost an issue? Co-existing DM or insulin resistance? Sibutramine contraindicated? NO YES Sibutramine NO Orlistat YES On metformin? YES Co-existing depression? NO Metformin NO Consider adding exenatide YES Consider bupropion YES/No

36. Case Application Benefit of medications without lifestyle changes is questionable Benefit of medications without lifestyle changes is questionable Sibutramine and orlistat likely cost prohibitive for this patient with Medicaid. Sibutramine and orlistat likely cost prohibitive for this patient with Medicaid. Consider changing anti-depressant to bupropion Consider changing anti-depressant to bupropion Consider adding metformin due to insulin resistance Consider adding metformin due to insulin resistance Gastric banding best option, but likely not covered Gastric banding best option, but likely not covered Gastric bypass next best option, but not without risk Gastric bypass next best option, but not without risk

37. Bibliography 1. Snow, V, Barry, P, Fitterman, N, et al. Pharmacologic and surgical management of obesity in primary care: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2005;142:525. 2. Arterburn, D, Crane, P, and Veenstra, D. The efficacy and Safety of Sibutramine for Weight Loss. Arch Intern Med 2004;164:994-1002. 3. Zhaoping, et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 2005;142:532-546. 4. Padwal R, Li SK, Lau DCW. Long-term pharmacotherapy for obesity and overweight. Cochrane Database of Systematic Reviews 2003, Issue 4. 5. Haddock CK, Poston WS, Dill PL, Foreyt JP, Ericsson M. Pharmacotherapy for obesity: a qualitative analysis of four decades of published randomized controlled trials. Int J Obes Relat Metab Disord 2002;26:262-73. 6. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27:155. 7. O’brien P et al. Treatment of mild to moderate obesity with laparoscopic adjustable gastric banding or an intensive medical program. Ann Intern Med 2006;144:625-633. 8. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients. JAMA 2006;295:761-775.

38. Bibliography Continued 9. Wadden TA, Berkowitz RI, Womble LG, et al. Effects of sibutramine plus orlistat in obese women following 1 year of treatment by sibutramine alone: a placebo-controlled trial. Obes Res 2000;8(6):431-7. 10. Kaya A, Aydin N, Topsever P, et al. Efficacy of sibutramine, orlistat, and combination therapy on short-term weight management in obese patients. Biomed Pharmacother 2004;58:582-7. 11. Sari R, Balci MK, Cakir M, et al. Comparison of efficacy of sibutramine or orlistat versus their combination in obese women. Endocr Res 2004;30(2):159-67. 12. A. Gokcel, Y. Gumurdulu, H. Karakose, E. Melek Ertorer, N. Tanaci, N. Bascil Tutuncu and N. Guvener. Evaluation of the safety and efficacy of sibutramine, orlistat, and metformin in the treatment of obesity. Diabetes Obes Metab 2002;4:49–55. 13. Knowler WC, Barrett-Connor E, Fowler SE et al. Reduction in incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393. 14. R.A. DeFronzo, R.E. Ratner, J. Han, D.D. Kim, M.S. Fineman and A.D. Baron, Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28:1092–1100. 15. Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and phamacotherapy for obesity. N Engl J Med 2005;353:2111- 20.